Individuals with the chronic mental disorders of schizophrenia or schizoaffective disorder (SZ) often exhibit long-term disability in critical everyday functional skills, including social and occupational functioning, residential maintenance, medication management, and basic self-care; these disabilities are largely unaffected by current treatments and are strongly related to cognitive dysfunction. Bipolar I disorder (BPI) shows some overlap with SZ in, e.g., psychotic symptoms and certain recently observed genetic associations. Individuals with BPI likewise suffer functional and cognitive disabilities, although to a lesser extent on the whole than those with SZ. Consistent with increasing emphasis by NIH and clinical researchers on amelioration of everyday functional disability, we will examine candidate genes for association with 1) state-of-the-art measures of functional capacity (reflecting skills required for real-world occupational outcomes) incorporated in the University of California at San Diego (UCSD) Performance-Based Skills Assessment (UPSA); and 2) the widely-adopted neuropsychological (NP) battery from the NIH MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia). The latter NP measures are known to relate to these performance-based measures and real world outcomes. UPSA and NP measures will be made at follow-up visits to an estimated 1005 Ashkenazi Jewish subjects already participating in Johns Hopkins University genetic studies (80% of total sample of 1256: 700 with SZ and 556 with BPI). An advantage in relying on this relatively-genetically-isolated population is greater genetic homogeneity. Genetic analyses for the 1005 follow-up subjects will rely on one or more functional capacity factors derived from the UPSA and MATRICS-NP. Additionally, the functional capacity factor(s) will be regressed on previously collected indicators of real-world disability in order to derive equation(s) predicting the former from the latter. These will in turn be used to create a proxy functional capacity index for all 1256 subjects, to be used in parallel genetic analyses on the larger sample. We anticipate that uncovering genetic associations with functional disability, independent of more widely studied symptom domains such as psychosis, will lead to increased understanding and research on the biological systems affecting this aspect of severe mental disorders, and eventual therapeutic progress in disability amelioration. [unreadable] [unreadable] [unreadable]